Curcumin based nanomedicines as efficient nanoplatform for treatment of cancer: New developments in reversing cancer drug resistance, rapid internalization, and improved anticancer efficacy

Highlights

• Development of versatile anticancer regimen is challenging due to tumor heterogeneity.

• Curcumin nanomedicines bring remarkable solution for cancer therapy.

• Nano-encapsulation is a promising approach to maximize anti-mutagenic efficacy of curcumin.

• Curcumin nanocarriers improve drug internalization and reverse cancer drug resistance.

Abstract

Background

Cancer is a group of diseases involving an abnormal growth of cells which tend to proliferate in an uncontrolled fashion and in some cases metastasize to the surrounding tissues (malignancy). Resistance to chemotherapy is typically intrinsic (heterogeneity); however, acquired resistance has also become prevelant due to multiple factors including expression of energy-dependent transporters causing expulsion of internalized drug contents extracellular, insensitivity of tumor cells to drug-induced apoptosis, and induction of drug-detoxifying mechanisms. Curcumin (CUR) has gained widespread recognition due to remarkable anticancer, anti-mutagenic, and anti-metastasizing potentials via downregulation of proliferation of cancer cells and induction of apoptosis. Nevertheless, pharmaceutical significance and therapeutic feasibility of CUR is restricted due to intrinsic physicochemical characteristics including poor aqueous solubility, inadequate biological stability, low bioavailability, and short half-life.

Scope and approach

Owing to these pharmaceutical limitations of CUR, nanodelivery systems have attained remarkable fascination in the recent years. Therefore, this review was aimed to overview and critically ponders recent developments in improving anticancer viability of CUR.

Key findings and conclusion

Critical analysis of the literature revealed that nanodelivery systems showed promising efficiency in achieving tumor specific targetability, maximizing internalization of drugs into cancer cells, mitigating tumor metastasis, as well as improving anticancer efficacy of CUR. Moreover, nanocarrier-mediated improved pharmacokinetics, drug accumulation, induced promising cytotoxicity, and enhanced anticancer efficacy by suppressing Egr-1 induction, Mitogen-activated protein kinase (MAPK) pathway, and protein tyrosine kinase (PTK) cascades while mitigating the progression of tumor, have also been discussed.

Introduction

Cancer is a group of diseases involving an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize to surrounding tissues. It tends to remain the major cause of fatalities worldwide with an expected forecast of increasing cancer incidences in coming decades, with 420 million new cases each year expected by 2025 (Zugazagoitia et al., 2016). In 2017, 1,688,780 new cases of cancer and 600,920 deaths associated with cancer have been projected to occur in the United States (Siegel, Miller, & Jemal, 2017). There have been predictions for 26 million new cancer cases worldwide with 17 million deaths by 2030 (Thun et al., 2009). Among several current cancer modalities, surgical intervention, radiation, and chemotherapy are most commonly employed (Peer et al., 2007). A major problem limiting the success of the most of the currently employed anticancer regimen is their non-specificity or non-selectivity towards tumor cells and tissues. This has resulted in terrific increase in occurrence of off-target effects in healthy tissues and organs. Generally, in anticancer therapy, the targeting and achievement of therapeutically active concentration of anticancer agents in tumor tissues pose substantial challenges and is associated with several severe adverse effects. This non-specificity or non-selectivity towards tumor cells and tissues creates toxicological problems that erect obstacles against the effective chemotherapy (Liang et al., 2010). Despite lacking of target specific targeting, most of the anticancer agents exhibit poor aqueous solubility due to their intrinsic hydrophobic nature. This leads to their lower absorption from the biological membranes and thus limit their therapeutic and clinical efficacy (Ünal, Öztürk, & Bilensoy, 2015). Therefore, delivering of anticancer drugs selectively and precisely to tumor tissues in therapeutic concentrations as well as improvement of their aqueous solubility are paramountly vital for rational treatment of cancer.

Due to several limitations associated with currently employed anticancer regimens as well as in search of alternative therapeutically effective anticancer regimen, researchers attempted the use of natural herbal medicines, phytomedicines, and therapeutically effective phytochemicals originated from the natural sources for anticancer therapy. For ancient times, natural herbal medicines and plants based phytochemical constituents have been widely utilized for the treatment of various human diseases. Natural products have gained noticeable medicinal importance during the last three decades as novel, safe, effective and economic therapeutic agents. Similarly, various scientific reports have indicated the potentials of plant-derived compounds for inhibition of different stages of tumorigenesis and associated inflammatory processes. These reports have highlighted the effectiveness of natural products for the treatment and management of various types of cancer (Newman, 2008; Newman, Cragg, & Snader, 2003; Solowey et al., 2014).

Polyphenols are naturally occurring compounds having multiple phenolic functional groups. More than 8000 polyphenolic compounds have been identified in various plant species. All plant phenolic compounds arise from a common intermediate, phenylalanine, or a close precursor, shikimic acid. Polyphenols may be classified into different groups as a function of the number of phenol rings that they contain and on the basis of structural elements that bind these rings to one another. The main classes include phenolic acids, flavonoids, stilbenes and lignans (Kondratyuk & Pezzuto, 2004; Pandey & Rizvi, 2009). Polyphenols have demonstrated promising anticancer and antioxidant activities against a wide range of cancer cells (Greenwell & Rahman, 2015). Their promising anticancer activity is associated with their ability to selectively induce apoptosis in cancer cells and tissues. The initiation and induction of apoptosis in cancer cells is associated through the regulation and mobilization of copper ions which bound to chromatin and cause induction of DNA fragmentation (Azmi et al., 2006). Other mechanisms associated with the anticancer potential of polyphenols include, their ability to interfere with proteins specifically present in cancer cells and selectively down-regulate proliferation of cancer cells. Moreover, anticancer agents can be altered through the polyphenol regulating acetylation, methylation or phosphorylation by direct bonding. For example, polyphenol treated cancer cells have shown significant suppression of the expression of tumor necrosis factor-α (TNF-α) through the interaction with various cellular pathways (Gupta et al., 2014). Fig. 1 shows various classes of polyphenols having promising anticancer activities.

Among several polyphenols exhibiting anticancer potential, curcumin (CUR) has shown remarkable anticancer efficacy against various types of cancer. CUR is a hydrophobic polyphenolic compound derived from the rhizomes of Curcuma longa. This natural compound has a long history to be used as a curry (turmeric) in East Asian countries. CUR belongs to the class of compounds known as “Curcuminoids” containing two other compounds demethoxycurcumin and bisdemethoxycurcumin (M Yallapu, Jaggi, & C Chauhan, 2013) (Fig. 2). CUR has gained remarkable recognition due to its versatile pharmacological activities including anti-inflammatory, antioxidant, wound healing, tissue regenerating, anti-mutagenic, and anticancer with low or no intrinsic toxicity to healthy cells (Kang et al., 2011; Kuttan et al., 1985; Polasa et al., 1992; Srimal & Dhawan, 1973). Moreover, substantial evidences have shown excellent ability of CUR analogs in alleviating and suppressing the generation, transformation, proliferation, and metastasis of various types of cancer cells including breast cancer, colon carcinoma, cervical cancer, stomach cancer, pancreatic cancer, and liver cancer (Kuttan et al., 2007, pp. 173–184; Shishodia, Chaturvedi, & Aggarwal, 2007). Taken together, CUR has shown a great promise as a chemo-preventive and therapeutic drug in treating hepatocellular carcinoma, possibly because of its potent anti-angiogenic activity and pro-apoptotic properties (Yoysungnoen et al., 2005).

Despite exhibiting excellent anticancer potential, the therapeutic efficacy and clinical applicability of CUR is limited due to its intrinsic physicochemical properties. CUR belongs to Biopharmaceutical Classification System (BSC) class II drugs, which exhibits poor aqueous solubility but high permeability. The poor aqueous solubility (0.0004 mg/mL at pH 7.3) and sensitivity at physiological pH (Yallapu, Jaggi, & Chauhan, 2012) significantly decrease their bioavailability and clinical efficacy. An oral administration of CUR (8–12 g daily) results in a very low plasma concentration (<1 μg/mL) and shows no significant therapeutic activity (Anand et al., 2007). Its rapid intestinal and hepatic metabolism is another pharmaceutical factor limiting its biopharmaceutical performance. When administered orally, approximately 60–70% of CUR gets excreted through feces. An aqueous suspension of CUR administered to rats at 2 g/kg body weight resulted in a plasma concentration of about 1 μg/mL in 1 h which drops rapidly below detectable limit within 5 h (Shoba et al., 1998). Moreover, it has lower cellular uptake or internalization which further reduce its therapeutic efficacy (Gurung et al., 2017). Despite its proved therapeutic efficacy in cancer treatment with low toxicity to humans and animals, CUR has not yet been approved as a therapeutic agent due to the above mentioned drawbacks. These drawbacks have been the real obstacles preventing CUR translation from labs to clinics. Among various strategies, a rational approach to improve the pharmaceutical significance of CUR is to improve its bioavailability, alleviate its biodegradation and metabolism, and increase its cellular internalization and targeting capacity toward cancer cells.

For the past few decades, nanotechnology has gained remarkable recognition due to their numerous physicochemical, pharmaceutical, and pharmacological features. Nanotechnology exploits the applications of materials in nano-size range for both drug delivery and diagnostic purposes. Drug nanocarriers possess several attractive features such as improved encapsulation or solubilization of pharmacological agents and their precise and selective delivery to the desired target sites (Ayumi, Sahudin, Hussain, Hussain, & Samah, 2018; Choudhury et al., 2018; Dong, Tao, Abourehab, & Hussain, 2018; Fan, Mohammed, Abourehab, & Hussain, 2018; Gorain et al., 2018; Pandey et al., 2018; Shao et al., 2016). Nanoencapsulation of CUR has also shown remarkable improvement in its anti-inflammatory, antioxidant, wound healing, and tissue regenerating efficacy (Hussain, Thu, Ng, Khan, & Katas, 2017, 2017). Moreover, their high surface to volume ratio enables modifications to surface functional groups for achieving drugs extensive stabilization and internalization, superior pharmacokinetics and decreased clearance from the body (Hussain et al., 2018; Safdar et al., 2017). Similarly, nanocarriers are capable of releasing the loaded drugs “on demand” in a fair controlled and sustained manner in response to stimuli or remote actuation (Gindy and Prud homme, 2009; Shao et al., 2016; Yu, Park, & Jon, 2012). Based on such nanocarriers, a large number of anticancer nanomedicines are currently in clinical or preclinical development stages. Some of the nanomedicines have been approved by the FDA and are currently available in the market (M Yallapu et al., 2013; Siddiqui, Adhami, & Christopher, 2012). Effective cancer therapy requires effective therapeutic concentrations of the drugs at tumor sites, which minimizes their side effects on healthy tissues. This review aims to critically discuss and summarize various nanocarrier-mediated strategies to improve CUR targeting to cancerous cells, rapid internalization, improved pharmacokinetic profile of anticancer drugs, improved clinical efficacy of nanomedicines, and to alleviate off-target effects of nanomedicines regimen.